The Loss and Gain of Functional Amino Acid Residues Is a Common Mechanism Causing Human Inherited Disease

Jose Lugo-Martinez, Vikas Pejaver, Kymberleigh A. Pagel, Shantanu Jain, Matthew E. Mort, David N. Cooper, Sean D. Mooney, Predrag Radivojac

Abstract: Author Summary Identifying the molecular changes caused by mutations is a major challenge in understanding and treating human genetic disease. To address this problem, we have developed a wide range of profiling tools designed to predict specific types of functional site from protein 3D structures. We then apply these tools to data sets of inherited disease-associated and putatively neutral amino acid substitutions and estimate the relative contribution of the loss and gain of functional residues in disease. Our results suggest that alterations of molecular function are involved in a significant number of cases of human genetic disease and are over-represented as compared to putatively neutral variants. Additionally, we use experimental data to show that it is possible to computationally identify the loss of specific functional events in disease pathogenesis. Finally, our methodology can be used to reliably identify the potential molecular consequences of disease-causing genetic variants and hence prioritize experimental validation.